PROJECT ONE SUMMARY/ABSTRACT Early identification of prodromes in neurodegenerative diseases is of great importance for understanding the course of and potential for interventions in progressive cognitive change. Prodromal Alzheimer's disease may manifest in multiple cognitive domains, including memory or executive deficits, making it difficult to distinguish from other prodromal pathophysiologies such as frontotemporal dementia. This project addresses this difficulty by combining structural and functional markers of network integrity with novel measures of white matter disruption using the recently developed NIH Human Connectome Project scanner. This state-of-the-art instrument was developed for high fidelity imaging of the integrity of white matter fiber tracts, but also allows conventional imaging. These technical advantages are leveraged by the project aims. The project focus is on subjects with subjective cognitive concerns or mild cognitive impairment exhibiting a phenotype of predominant executive dysfunction or of predominant memory deficits. Aim 1 will test the hypothesis that these two cognitive phenotypes will be associated with structural and functional connectivity measures of the integrity in different networks. Aim 2 will test the hypothesis that novel measures of white matter integrity using diffusion imaging on the Connectome Project scanner will improve sensitivity to early impairments in the these two cognitive phenotypes when paired with the structural and functional connectivity measures developed in Aim 1. Because of the novelty of the Connectome methods, we will assess the sensitivity of fiber tract identification and integrity compared to conventional methods across a 3-year follow-up interval in a subset of subjects. The project addresses a growing need for early identification and differential diagnosis of individuals who will go on to develop different neurodegenerative diseases so that they can be targeted for participation in clinical trials or lifestyle interventions. Successful completion of the aims will contribute novel neuroimaging markers of prodromal neurodegenerative diseases and will further scientific knowledge of the relationship between functional network integrity and the integrity of fiber tracts connecting key nodes within a network.